# Whole-Exome Sequencing Revealed a Pathogenic Germline Variant in the Fumarate Hydratase Gene, Leading to the Diagnosis of Hereditary Leiomyomatosis and Renal Cell Cancer

## TL;DR

A 60-year-old woman with skin tumors was diagnosed with a hereditary cancer syndrome using whole-exome sequencing, revealing a gene variant linked to kidney cancer risk.

## Contribution

The study demonstrates the utility of whole-exome sequencing in diagnosing hereditary leiomyomatosis and renal cell cancer through a novel germline variant in the FH gene.

## Key findings

- A pathogenic germline variant (c.290G>A, p.Gly97Asp) in the FH gene was identified in a patient with multiple cutaneous leiomyomas.
- The patient's hysterectomy for uterine myoma supported the diagnosis of hereditary leiomyomatosis and renal cell cancer.
- No kidney tumors were detected, highlighting the importance of genetic testing for early detection of renal cancer.

## Abstract

The diagnosis of hereditary skin tumors is difficult for “old” diagnostic tools such as immunohistochemistry. Whole-exome sequencing analysis as a “new” diagnostic tool enables us to make a final diagnosis in spite of unknown hereditary diseases in the past. Hereditary leiomyomatosis and renal cell cancer are autosomal dominant hereditary cancer syndromes characterized by uterine myomas, cutaneous leiomyomas, and aggressive renal cell cancer. The syndrome is associated with pathogenic germline variants in the fumarate hydratase gene. Herein, we demonstrate a pathogenic germline variant of the fumarate hydratase gene in a 60-year-old woman with multiple cutaneous leiomyomas, leading to the diagnosis of hereditary leiomyomatosis and renal cell cancer. Whole-exome sequencing analysis using genomic DNA extracted from peripheral blood leukocytes revealed one germline variant in the FH gene on chromosome 1 (c.290G>A, p.Gly97Asp). She received total hysterectomy due to uterine myoma, which strongly supported the diagnosis. No tumor was detected in her kidney by computed tomography and ultrasound examination. Genetic examination for the mutation of the fumarate hydratase gene is important in order to reach the correct diagnosis and to detect renal cancer at its early stage.